Vitamin E (alpha-tocopherol) formulations constitute a multi-million dollar US market. Tocopherol supplements are widely used for presumptive health benefits and antioxidant properties; but these supplements are almost exclusively restricted to a-tocopherol. Tocopherol biology is complicated by the fact that other tocopherol forms (beta-, gamma-, and delta-tocopherol), structurally distinct from a-tocopherol, exist as part of the natural human diet. Moreover tocopherols are metabolized in vivo to yield carboxyethyl-hydroxyl chromane (CEHC) products that have been insufficiently studied. Recent studies suggest that gamma-tocopherol and its analogs possess anti-inflammatory and other activities that could be harnessed therapeutically. Scientists at the Oklahoma Medical Research Foundation (OMRF) have established a partnership with Encore Pharmecuticals, Inc. for the purpose of developing novel tocopherol-based structures with superior anti-inflammatory and other activities. We have begun to systematically evaluate structure-activity relationships among natural tocopherol analogs, their CEHC metabolites, and synthetic derivatives, with the goal of determining features that impart biological potency. The ultimate purpose of this endeavor is to develop novel, patentable compounds that inhibit neuroinflammatory reactions within the centralnervous system. Toward this end we propose the following SPECIFIC AIMS. SPECIFIC AIM 1: An initial series ofeleven new CEHC derivatives will be synthesized in order to determine whether rational derivatization of the 3, 4 and 5 positions of the chromane head group will improve bioactivity. Derivatives will be designed to combine beneficial features of the best first-generation molecules; and to systematically test the significance of substituent electronics, sterics and polarity on compound bioactivity. SPECIFIC AIM 2: The compounds synthesized under SPECIFIC AIM I will be evaluated for antagonism of TNFa-stimulated microglial activation using an established EOC-20 microglial cell culture assay. Nitrite output and prostaglandin E2 (PGE2) production will be used as indicators of anti-neuroinflammatory activity. Efficacy of CEHC derivatives will be compared with that of benchmark nonsteroidal anti-inflammatory drugs. The goal of this Phase I application is to identify two lead CEHCs for treating neuroinflammatory disease. During Phase II these lead agents will be further evaluated in a murine model for amyotrophic lateral sclerosis (ALS), the G93A-SOD1 transgenic mouse, which demonstrates a robust neuroinflammatory disease profile. Success in the G93A-SOD1 mouse model and confirmatory testing in a relevant mouse model of Alzheimer's disease (AD) will justify pursuit of investigational new drug (IND) status.